Insulin degludec improves long-term glycaemic control similarly to insulin glargine but with fewer hypoglycaemic episodes in patients with advanced type 2 diabetes on basal-bolus insulin therapy.

The aim of the present study was to compare the long-term safety and efficacy of insulin degludec with those of insulin glargine in patients with advanced type 2 diabetes (T2D) over 78 weeks (the 52-week main trial and a 26-week extension). Patients were randomized to once-daily insulin degludec or insulin glargine, with mealtime insulin aspart ± metformin ± pioglitazone, and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l (70-88 mg/dl). After 78 weeks, the overall rate of hypoglycaemia was 24% lower (p = 0.011) and the rate of nocturnal hypoglycaemia was 31% lower (p = 0.016) with insulin degludec in the extension trial set, while both groups of patients achieved similar glycaemic control. Rates of adverse events and total insulin doses were similar for both groups in the safety analysis set. During 18 months of treatment, insulin degludec + mealtime insulin aspart ± oral antidiabetic drugs in patients with T2D improves glycaemic control similarly, but confers lower risks of overall and nocturnal hypoglycaemia than with insulin glargine treatment.

Insulin degludec improves glycaemic control with lower nocturnal hypoglycaemia risk than insulin glargine in basal-bolus treatment with mealtime insulin aspart in Type 1 diabetes (BEGIN(®) Basal-Bolus Type 1): 2-year results of a randomized clinical trial.

AIMS: The goal of this study was to compare the long-term safety and efficacy of the basal insulin analogue, insulin degludec with insulin glargine (both with insulin aspart) in Type 1 diabetes, over a 2-year time period. METHODS: This open-label trial comprised a 1-year main trial and a 1-year extension. Patients were randomized to once-daily insulin degludec or insulin glargine and titrated to pre-breakfast plasma glucose values of 3.9-4.9 mmol/l. RESULTS: The rate of nocturnal confirmed hypoglycaemia was 25% lower with insulin degludec than with insulin glargine (P = 0.02). Rates of confirmed hypoglycaemia, severe hypoglycaemia and adverse events, and reductions in glycated haemoglobin and fasting plasma glucose were similar between groups. Despite achieving similar glycaemic control, insulin degludec-treated patients used 12% less basal and 9% less total daily insulin than did insulin glargine-treated patients (P < 0.01). CONCLUSIONS: Long-term basal therapy using insulin degludec in Type 1 diabetes required lower doses and was associated with a 25% lower risk for nocturnal hypoglycaemia than insulin glargine.

Leptin and its relation to obesity and insulin in the SHR/N-corpulent rat, a model of type II diabetes mellitus.

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic animal model that exhibits obesity, metabolic features of hyperinsulinemia, hyperglycemia, and hyperlipidemia, which are characteristic of type II diabetes and mild hypertension. To determine the role of leptin, the protein product of the ob gene, in the development of obesity and diabetes in this model, we measured steady-state circulating levels of leptin in obese and lean SHR/N-cp rats and examined the relation between plasma leptin levels and metabolic variables at the stage of established obesity in these animals. Mean fasting plasma leptin concentration was 8-fold higher in obese than in lean rats (p < 0.01). This was associated with a 6-fold elevation in plasma insulin in the obese group. Fasting levels of plasma glucose, cholesterol, and triglyceride were all significantly higher in obese rats than in lean controls. Spearman correlation analysis showed a significant positive correlation between plasma leptin concentration and body weight among the animals (r = 0.73, p < 0.01). Similarly, plasma insulin concentration was significantly correlated with BW in all animals (r = 0.54, p < 0.05). There was also a significant positive correlation between plasma leptin and plasma insulin in the entire group (r = 0.70, p < 0.01). However, this relationship was significant only for lean rats but not for obese rats (r = 10.59, p < 0.05 for lean rats, and r = 0.23, p = NS, for obese rats). Plasma leptin also correlated positively with fasting plasma glucose (r = 0.75, p < 0.05), total cholesterol (r = 0.63, p < 0.05), and triglyceride (r = 0.67, p < 0.05). The marked elevation of plasma leptin in obese SHR/N-cp rats suggests that obesity in this animal model is related to up-regulation of the ob gene. Circulating leptin appears to be one of the best biological markers of obesity and that hyperleptinemia is closely associated with several metabolic risk factors related to insulin resistance in the diabesity syndrome.

Factors affecting the efficiency of embryo cryopreservation and rederivation of rat and mouse models.

The efficiency of embryo banking for rat and mouse models of human disease and normal biological processes depends on the ease of obtaining embryos. Authors report on the effect of genotype on embryo production and rederivation. In an effort to establish banks of cryopreserved embryos, they provide two databases for comparing banking efficiency: one that contains the embryo collection results from approximately 11,000 rat embryo donors (111 models) and another that contains the embryo collection results from 4,023 mouse embryo donors (57 induced mutant models). The genotype of donor females affected the efficiency of embryo collection in two ways. First, the proportion of females yielding embryos varied markedly among genotypes (rats: 16-100 %, mean =71 %; mice: 24-95 %, mean =65 %). Second, the mean number of embryos recovered from females yielding embryos varied considerably (rats: 4-10.6, mean =7.8; mice 5.3-32.2, mean =13.7). Genotype also affected the efficiency of rederivation of banked rat and mouse embryos models by embryo transfer. For rats, thawed embryos (n =684) from 33 genotypes were transferred into 66 recipient females (pregnancy rate, 78 %). The average rate of developing live newborns for individual rat genotypes was 30 % with a range of 10 to 58 %. For mice, thawed embryos (n =2,064) from 59 genotypes were transferred into 119 pseudopregnant females (pregnancy rate: 76 %). The average rate of development of individual mouse genotypes was 33 % with a range of 11 to 53 %. This analysis demonstrates that genotype is an important consideration when planning embryo banking programs.

BALB/c.CBA/N mice carrying the defective Btk(xid) gene are resistant to pristane-induced plasmacytomagenesis.

The X-chromosome from the CBA/N mouse which carries the defective Bruton's tyrosine kinase (Btk) allele (Xxid) has been introgressively backcrossed onto the plasmacytoma (PCT) induction-susceptible BALB/cAN. Inbred BALB/c.CBA/N-xid/xid (C.CBA/N) mice raised and maintained in our conventional colony were given three 0.5 ml injections of pristane and were highly refractory to PCT induction. Only one PCT was found among 59 mice followed for > or =300 days. Twenty mice were examined at day 200 for foci of plasma cells in the oil granuloma. Ten mice had small foci of plasma cells, most of which were plasmacytotic, embedded in the inflammatory oil granuloma. In one there were multiple foci, but most of the mice had only one or two foci. F1 hybrid XxidY males derived from CBA/N females crossed to BALB/cAnPt were also resistant to PCT induction, while heterozygous and homozygous XY males were susceptible. C.CBA/N mice can develop extensive mucosal plasma cells as well as plasma cell accumulations in oil granuloma tissue, but the precursors of these plasma cells do not give rise to PCT in genetically susceptible hosts. The failure of C.CBA/N mice to develop PCT is probably due to the elimination of B cell clones that can be perpetuated by repeated exposure to thymus-independent type 2 antigens.

Long-term effects of perindopril on metabolic parameters and the heart in the spontaneously hypertensive/NIH-corpulent rat with non-insulin-dependent diabetes mellitus and hypertension.

The spontaneously hypertensive/NIH-corpulent (SHR/N-cp) rat is a genetic model that exhibits both non-insulin-dependent diabetes mellitus (NIDDM) and hypertension. To determine the impact of long-term treatment with the long-acting angiotensin-converting enzyme (ACE) inhibitor perindopril (PE) on the glucose metabolism, lipid levels, and heart in this model, studies were performed in three groups of SHR/N-cp rats maintained on a diet containing 54% carbohydrate with 18% sucrose and 36% starch. One group of obese rats received PE (0.5 to 1.0 mg/kg body weight/d) for 3 to 4 months, a second group of obese rats received no treatment, and a third group of lean rats were used as controls. The mean systolic blood pressure (SBP) increased gradually in both untreated obese and lean rats, with lean animals showing slightly higher levels compared with untreated obese rats. By contrast, SBP was reduced to normal levels in PE-treated obese rats throughout the treatment period. Compared with lean rats, obese rats showed significantly higher body weight and fasting serum levels of glucose, insulin, total cholesterol (TC), and triglyceride (TG). However, no significant differences were observed in these metabolic parameters between PE-treated and untreated obese rats. Plasma renin activity measured at the end of the treatment period was significantly higher in PE-treated rats compared with untreated obese and untreated lean rats. The mean heart weight and left ventricular weight, expressed in absolute terms or indexed to body weight, were significantly lower in PE-treated versus untreated obese and untreated lean rats. To further determine whether glucose metabolism is directly affected by PE treatment, in vitro glycogen synthesis was evaluated in isolated soleus muscles obtained from three additional groups of animals. The basal rate of muscle glycogen synthesis was significantly lower in obese compared with lean rats (P < .05), but did not differ between PE-treated and untreated obese rats. Maximal insulin-stimulated glycogen synthesis increased threefold in PE-treated obese rats, but this increase did not differ from the increases observed in untreated obese and lean rats. In conclusion, the present study shows that long-term PE treatment in obese SHR/N-cp rats with NIDDM and hypertension effectively controlled systemic arterial pressure and resulted in a significant reduction in left ventricular weight. However, these favorable effects of PE were not associated with significant improvement in glucose tolerance, hyperinsulinemia, and hyperlipidemia in this model. PE also had no direct stimulatory effects on either basal or insulin-mediated glycogen synthesis in the isolated soleus muscle of obese rats, perhaps because of the severe insulin-resistant state of the animals. Our results support the clinical observations that antihypertensive therapy with ACE inhibitors has neutral effects on glucose metabolism and insulin sensitivity in patients with combined hypertension and NIDDM.

The rat corpulent (cp) mutation maps to the same interval on (Pgm1-Glut1) rat chromosome 5 as the fatty (fa) mutation.

The autosomal recessive obesity mutations fatty (fa) and corpulent (cp) arose in separate rat strains, 13M and Koletsky, respectively. By complementation analysis, the two mutations appear to be in the same gene. The somewhat different phenotypes of fa/fa and cp/cp animals probably reflect the fact that the mutations are segregating on different rat strains. The fa mutation has been mapped to the interval between Pgm1 and Glut1 on rat Chr 5, but cp has not been mapped genetically. We mapped cp in 30 obese progeny of a LA/N-BN cp/+ intercross using microsatellite markers for these flanking genes. Cp maps to the same genetic interval as rat fa and mouse db. Cp is flanked by Glut1 and Pgm1: Pgm1-------- cp -------- Glut1 map distance (cM) 1.67 6.67 Thus, cp and fa map to the same approximately 8 cm interval of the rat genome. In conjunction with the complementation studies alluded to above, these findings indicate that cp and fa are mutations in the same gene (Lepr).

Early upregulation of medium neurofilament gene expression in developing spinal cord of the wobbler mouse mutant.

Homozygous wobbler mouse mutants develop a progressive paralysis due to spinal motoneuron degeneration. To understand the molecular aspect underlying the genetic defect we have studied the embryonic (from E13) and postnatal expression of the three neurofilament and choline acetyltransferase genes in each member from several wild-type (wt) and wobbler (wr) progenies. There are no variations among wt littermates at all ages studied. In contrast, analyses of neurofilament mRNA reveals a 3-4-fold increase of medium neurofilament (NFM) mRNA in wobbler mice (wr/wr). The pattern of increased NFM mRNA during development, prior to the appearance of the wobbler phenotype, among littermates (from heterozygous carriers) conforms to a mendelian inheritance of a single gene defect 1:2:1 (wr/wr:wr/+:+/+). Light and heavy neurofilament mRNA levels are also increased later in development exclusively in those individuals with high NFM mRNA values indicating that increase of the latter is associated with increase of the light and heavy subunit expression. Also NF proteins are increased. Expression of choline acetyltransferase gene is instead always comparable to normal control. Our study provides novel insights into the nature of the wobbler defect, strengthening the hypothesis that neurofilament accumulation plays a pivotal role in the etiopathogenesis of motoneuron degeneration.

Development and characteristics of a new strain of obese hyperinsulinemic and hyperlipidemic Dahl salt-sensitive rat. The Dahl salt-sensitive/NIH-corpulent rat.

A new congenic rat strain, the Dahl salt-sensitive/NIH-corpulent (DSS/N-cp) rat, has been developed to study the role of obesity and type of dietary carbohydrate in the development of hypertension and its complications. Three groups (n = 6) of young male obese and lean DSS/N-cp rats were fed diets containing either 54% sucrose, 18% sucrose plus 36% starch, or 54% starch, with 0.1% dietary sodium for 12 weeks. Regardless of the diet, obese and lean rats showed mildly elevated systolic blood pressure (SBP), being significantly higher in obese than in lean rats (SBP 156 +/- 5 mm Hg v 141 +/- 3 mm Hg, P < .05). However, SBP was not different between the three diet groups. Levels of serum insulin, triglyceride, and cholesterol as well as urinary protein excretion were significantly higher in obese than in lean rats. Obese rats fed the sucrose diets as compared to the starch diet, had higher serum insulin and lipid levels, but had lower body weights and higher serum creatinine levels. Histopathologic examination of tissues from different organs revealed a vasculopathy seen almost exclusively in obese rats fed the sucrose diets. Vascular lesions were characterized by subintimal fibrin deposition, fibrinoid necrosis, and cell proliferation with "onion skinning" in small arteries and arterioles of kidneys, intestine, pancreas, and testes.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine esterase and peripherin mRNA level decrease in wobbler mouse.

Homozygote wobbler mice develop motoneurone degeneration. Throughout development the expression of choline acetyltransferase, of trkC receptor and F3 adhesion molecule genes is similar in wobbler and wild-type spinal cord. Acetylcholinesterase mRNA level instead is decreased to about 50% with respect to wild-type values in one forth of P5 and P10 wobbler progeny, putative wr/wr individuals; at P21 its expression is equally highly reduced in known homozygotes and it is reduced to 35% of normal values in about one half of the progeny, putative heterozygotes. Thus, similarly to medium neurofilament gene over-expression, reduced acetylcholinesterase gene expression is an early molecular marker for the wobbler mutation before onset of the illness.

Differences in response to an acoustic startle stimulus among forty-six rat strains.

The startle response to intense environmental stimuli is found in most, if not all, animal species. Previous studies have shown that selected rodent strains differ in startle response to an acoustic stimulus, suggesting genetic variability. The current experiment was designed to extend these differences to a wider range of rat strains. Forty-six inbred and outbred rat strains were studied. These strains exhibited differences in both the mean amplitude of the startle response and the rate of habituation to startle stimuli over repeated trials. In addition, there was a significant relationship between these measures. These results suggest that robust phenotypic differences in startle response exist among rat strains. As previous investigations have demonstrated a direct relationship between the startle response and other behavioral end points, the use of strain differences in startle response may be an effective way to determine genetic contributions to specific behavioral responses.

Recruitment of antigen-nonspecific cells plays a pivotal role in the pathogenesis of a T cell-mediated organ-specific autoimmune disease, experimental autoimmune uveoretinitis.

Experimental autoimmune uveoretinitis (EAU) is a prototypic T cell-mediated autoimmune disease, whose target tissue is the neural retina, that is used as a model for a number of human blinding ocular diseases of a presumed autoimmune nature. EAU in rats can be induced by adoptive transfer of small numbers of retinal antigen-specific CD4+ T cell lines. Although recruitment mechanisms were assumed to play a role in the immunopathogenesis of uveitis, there is no direct evidence that would permit assessment of the importance of recruited non-antigen-specific T cells in retinal autoimmunity. In the present study, we addressed this question by using congenitally athymic Lewis rats (LEW.rnu/rnu), that are deficient in functional endogenous T cells, but are otherwise syngeneic with the euthymic Lewis rats that develop characteristically severe EAU. The uveitogenic stimulus was delivered in the form of phenotypically and functionally homogeneous pathogenic T cell lines, specific to the major pathogenic epitope of either the intracellular photoreceptor protein, S-Ag, or the extracellular photoreceptor matrix protein, IRBP. Depending on the T cell line used, EAU in athymic rats was either drastically reduced in severity (IRBP), or essentially absent (S-Ag). Susceptibility was restored when the athymic animals were reconstituted with immunocompetent T cells from syngeneic euthymic donors. While the intraocular infiltrate in euthymic rats was predominantly lymphocytic, with smaller numbers of monocyte/macrophages and even fewer neutrophils, the sparse infiltrate in athymics was largely monocytic, and with a relatively high proportion of neutrophils and eosinophils. Reconstituted animals had an intermediate histological picture with respect to the infiltrating cell types and disease severity. Our data are consistent with the interpretation that recruitment of naive T cells constitutes an amplification mechanism that is central to the expression and pathogenesis of uveitis. The extent of dependence on this phenomenon appears to be influenced by the antigenic specificity of the T cell line, and could be connected to the 'accessibility' of the target antigen in vivo.

The origin of the autoimmune disease-resistant LER rat: an outcross between the buffalo and autoimmune disease-prone Lewis inbred rat strains.

The Lewis (LEW) rat strain is highly susceptible to a large number of experimentally induced inflammatory and autoimmune diseases. The Lewis resistant (LER) rat strain, which reportedly arose as a spontaneous mutation in a closed colony of LEW rats, is resistant to many of these disorders. The mechanism of resistance is not yet clear. We report the analysis of 19 simple dinucleotide repeat polymorphisms in 13 rat strains including the LEW/N and LER/N rat strains. The LEW/N and LER/N alleles were the same in only 42% of cases. For all of the other polymorphisms, the LER/N and Buffalo (BUF/N) rat strain alleles were identical. These data provide evidence that the LER strain did not arise as a spontaneous mutation in the LEW strain but is the result of an outcross between the LEW and BUF rat strains. The LER rat strain is now a recombinant inbred rat strain. This information should facilitate the genetic analysis of the loci responsible for resistance to experimental autoimmune disease in the LER rat.

Genetic mapping of the athymic nude (RNU) locus in the rat to a region on chromosome 10.

The nude trait in the rat is transmitted in an autosomal recessive manner and is associated with thymic aplasia, T-cell deficiency, and hairlessness. Congenic rats homozygous for the RNU (Rowett nude) locus are important models in the study of inflammatory disease, tumor growth, and transplant rejection. The RNU locus has not been previously mapped, and the nature of the gene product is unknown. To determine the map location of this gene, a single F344.rnu/rnu (athymic nude congenic Fischer rat) male congenic rat was bred with 3 LEW/N (NIH stock Lewis rat) female rats to produce F1 progeny. Twelve F1 brother-sister breeding pairs were established. Forty-nine phenotypically nude F2 offspring (198 total) were obtained. Linkage analysis done on F2 DNA revealed highly significant cosegregation between the nude phenotype and eight polymorphic markers located on Chromosome (Chr) 10. The tightest linkages were with: MYH3 (embryonic, skeletal myosin heavy chain) and SHBG (sex hormone-binding globulin), giving 2 point lod scores of 20.2, and 20.0, respectively. The map order and map distances, determined by multipoint linkage calculations, were: RR24-(16.1 cM)-MYH3-(3.5 cM)-SHBG-(4.7 cM)-RNU-(11.9 cM)-F16F2-(24.1 cM)-CLATP (citrate lyase ATPase)-(2.4 cM)-ACE (angiotensin converting enzyme)/PPY (pancreatic polypeptide)-(14.1 cM)-RR1023. The position of the RNU locus in the rat corresponds closely with that of the recently reported nu locus in the mouse. This finding suggests that the nude phenotype in the rat and the mouse arise from defects in homologous genes.

Lymphoblastic lymphoma in a colony of N:NIH(S)-bg-nu-xid mice.

During a 1-year period, 28 animals from a breeding colony of N:NIH(S)-bg-nu-xid mice were discovered to have rapidly enlarging subcutaneous swellings in the ventral, cervical, and axillary regions. Five of the mice also had hind limb paresis. Twenty-two of the mice were heterozygous nude females, five were homozygous nude males, and one was a homozygous nude female. All of the above mice were homo- or hemizygous for the beige and X-linked immunodeficiency mutations. The average age of the mice was 8.3 months. Generalized enlargement of the peripheral and internal lymph nodes was present at the time of necropsy examination. Other lesions commonly noted at necropsy included splenomegaly (15 mice), pale and thickened ventral lumbar spinal musculature (11 mice), and opaque, thickened meninges of the brain (10 mice). Histologic examination consistently disclosed infiltrates of neoplastic lymphoblasts in multiple tissues including lymph nodes, spleen, bone marrow, and meninges of the brain and spinal cord. The cells were positive for IgG on immunofluorescent staining, suggesting that the tumors were of B cell origin. The neoplasms observed in these mice have several similarities to tumors found in immunodeficient humans, suggesting that these mice may serve as useful animal models of lymphoma.

Lack of antibody specificity by mouse trophectoderm during immunosurgery.

Immunosurgery of blastocyst-stage embryos is an effective procedure for isolating the inner cell mass. The ability of rabbit sera antibodies produced to interspecific types of cells to bind to mouse trophectoderm antigens and mediate complement-reactive lysis was investigated. Fifty hatched and 25 expanded blastocysts per treatment were exposed to 1 of 7 heat-inactivated polyclonal antibodies (1: 10 DMEM dilution) produced in rabbits to mouse brain cells (MBr), mouse lymphocytes (MLy), rat lymphocytes (RLy), hamster lymphocytes (HLy), cattle splenocytes (CSp), sheep splenocytes (SSp), and pig splenocytes (PSp). After subsequent incubation in a guinea pig complement solution (1: 16 dilution) the embryos were assessed for trophectoderm lysis, and the inner cell masses were pipetted free of cellular debris. Fewer (P<0.01) hatched blastocysts were lysed completely when treated with RLy (60%), CSp (50%) and PSp (14%) antibodies compared the other treatment groups (100%). A similar response was observed with expanded blastocysts, with the exception that even fewer (P<0.01; RLy, 24%; CSp, 40%; PSp, 0%) were lysed completely. Forty percent of the PSp expanded blastocysts experienced no lysis, which was different (P<0.01) than in all the other treatments. Secondary experiments were performed to explain the cause of partial lytic response. Overall, the results indicate that interspecific antibodies can bind to murine trophectoderm surface antigens and mediate immunosurgical inner cell mass isolation, although the trophectoderm lytic response varied with antibody source.

Reversal of immune dysfunction in osteopetrotic rats by interferon-gamma: augmentation of macrophage Ia expression and lymphocyte interleukin-2 production and proliferation.

Lymphocytes from osteopetrotic (op) rats, compared to their normal (n) littermates, exhibit defective immune functions associated with their inability to resorb bone. Among these immune defects are the failure of their spleen cells to proliferate normally to mitogens and to generate IL-2. Addition of exogenous IL-2 failed to reverse the suppressed proliferation in the op spleen cells, indicating that additional defects were involved in the suppression. Phenotypic analysis of cellular constituents of op and n spleens revealed that the percentages of T cells, macrophages, and IL-2 receptor positive cells were not different. Furthermore, there was no difference in CD4 (W3/25) and CD8 (OX8) cells. However, the Ia+ (OX3) cells in the op spleen represented less than 50% of those found in the n spleen, but the op had higher levels of transferrin receptor (OX26). On the basis of the ability of interferon-gamma (IFN-gamma) to increase Ia expression, this cytokine was added to op spleen cells (10-50 U/ml) and found to increase the number of Ia+ cells to the level found in n spleen cells. Moreover, pretreatment of op spleen cells with IFN-gamma restored their ability to proliferate to mitogens and their responsiveness to IL-2. Not only did IFN-gamma reverse the defective response to IL-2, but it also augmented the defective IL-2 production by op spleen cells. Taken together, these findings demonstrate that IFN-gamma can reverse many of the impaired immune functions characteristic of op spleen cells in vitro. Furthermore, these data suggest that IFN-gamma may provide an important avenue of treatment in these animals that may contribute to restoration of normal bone resorption.

FVB/N: an inbred mouse strain preferable for transgenic analyses.

FVB/N mice offer a system suitable for most transgenic experiments and subsequent genetic analyses. The inbred FVB/N strain is characterized by vigorous reproductive performance and consistently large litters. Moreover, fertilized FVB/N eggs contain large and prominent pronuclei, which facilitate microinjection of DNA. The phenotype of large pronuclei in the zygote is a dominant trait associated with the FVB/N oocyte but not the FVB/N sperm. In experiments to generate transgenic mice, the same DNA constructs were injected into three different types of zygotes: FVB/N, C57BL/6J, and (C57BL/6J x SJL/J)F1. FVB/N zygotes survived well after injection, and transgenic animals were obtained with efficiencies similar to the F1 zygotes and much better than the C57BL/6J zygotes. Genetic markers of the FVB/N strain have been analyzed for 44 loci that cover 15 chromosomes and were compared with those of commonly used inbred strains. In addition to the albino FVB/N strain, pigmented congenic strains of FVB/N are being constructed. These features make the FVB/N strain advantageous to use for research with transgenic mice.

Effect of dietary carbohydrate on liver and kidney enzyme activities and plasma amino acids in the LA/N-cp rat.

Twenty obese and 20 lean LA/N-cp male rats and 20 male Sprague-Dawley rats were fed a diet containing either 54 percent sucrose or starch for six weeks. After a 14-16 hour fast, rats were killed. Liver and kidney enzyme activities were determined in the LA/N-cp rats while plasma urea and selected amino acids were determined in all rats. Liver glucose-6-phosphatase (G6PASE), fructose-1,6-bisphosphatase (FBPASE), phosphoenolpyruvate carboxykinase (PEPCK), glucose-6-phosphate dehydrogenase (G6PDH), 6-phosphogluconate dehydrogenase (6PGDH), malic enzyme (ME), glucokinase (GK), pyruvate kinase (PK), phosphofructokinase (PFK), glutamic-oxaloacetic-transaminase (GOT), glutamic-pyruvic transaminase (GPT), arginase (ARGASE), arginine-synthase (ARG-SYN) and ornithine transcarbamylase (OTC) levels were significantly affected by phenotype (obese greater than lean). All the above changes in enzyme levels were exaggerated by sucrose-feeding with the exception of PK, PFK, GOT, GPT, ARGASE and ARG-SYN. Kidney cortex G6PASE, PEPCK and ARGASE activities were higher in the obese rats as compared to the lean littermates. Sucrose feeding resulted in higher cortex G6PASE, FBPASE and PEPCK as compared to starch-fed rats. A phenotype effect was noted with plasma glutamate, urea, leucine, isoleucine and valine (obese greater than lean) and a diet effect was seen with aspartate, phenylalanine, leucine and valine (sucrose greater than starch) concentration. Sprague-Dawley rats had higher plasma urea and lower alanine than lean LA/N-cp males. Metabolic obesity in the LA/N-cp rat appears to involve an elevated capacity for pathways of glycolysis, gluconeogensis, lipogenesis and amino acid catabolism in the liver.

A difference in mortality between two strains of jaundiced rats.

Homozygous Gunn rats lack bilirubin glucuronyltransferase, become jaundiced, and often develop kernicterus, thus providing a model for neonatal hyperbilirubinemia. Two new, inbred rat strains that carry the Gunn mutation are described. These were developed by breeding the mutant Gunn gene (j) into the RHA/N and ACI/N strains, producing the new lines, which were designated RHA/N-j and ACI/N-j. Liver assay confirmed the absence of transferase activity in jaundiced rats from both of the new strains, but marked differences in mortality between the strains were observed. The mortality of jaundiced RHA/N-j rats through 8 weeks was the same as that of their nonjaundiced littermates (20%). In contrast, mortality of jaundiced ACI/N-j rats was distinctly greater than that of their nonjaundiced littermates (81% vs 34%, P less than .001). Signs of kernicterus such as ataxia were much more frequent in jaundiced ACI/N-j rats than in jaundiced RHA/N-j rats (73% vs 11%, P less than .001). Both strains had comparable albumin concentrations through 8 weeks of age. Serum bilirubin concentrations were also comparable, except for a small but significant difference at 20 days of age (ACI/N-j = 294 mumols/L, RHA/N-j = 248 mumols/L, P less than .01). Similarly, the bilirubin-to-albumin ratios were comparable except for a significantly higher ratio at 20 days of age in the ACI/N-j rats (ACI/N-j = 0.70, RHA/N-j = 0.51, P less than .01). Thus, the RHA/N-j strain is unusual in that the jaundiced animals remain healthy. Conversely, the ACI/N-j animals demonstrate a high incidence of kernicterus with mortality.(ABSTRACT TRUNCATED AT 250 WORDS)